5-Hydroxytryptamine (5-HT) is an important signalling molecule in the human body, and has important effects both as a neurotransmitter and as a locally acting signalling molecule with e.g. vasoactive effects. During the past 20 years 14 different 5-HT receptors have been identified and classified into 7 different subgroups (5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7), based on structural and pharmacological criteria as well as signal transduction properties. Additional diversity arises from e.g. alternative splicing of e.g. 5-HT4 (e.g. 5-HT4(a), 5-HT4(b) etc.) and 5-HT7 receptors, and of RNA editing of e.g. 5-HT2C receptors. 5-HT4 is found to play a central role in diseases in organs like the heart, the gastrointestinal system, the urinary bladder and central nervous system (CNS).
5-HT4 receptor modulators, agonists and antagonists alike, are found to be useful for the treatment of a variety of diseases such as gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome, constipation, dyspepsia, oesophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, and cardiovascular disorders such as cardiac failure and heart arrhythmia. Further gastrointestinal disorders suitable for prophylaxis or treatment of the symptoms of Irritable Bowel Syndrome, including abdominal pain and disrupted colonic motility.
Since 5-HT4 receptors are located both inside and outside the CNS, 5-HT4 receptor agonists and antagonists will have effects both inside and outside the CNS, unless their design prevents their access to or causes them to preferentially localise to only one of these compartments. When addressing 5-HT4 receptors located outside the CNS, effects on receptors inside the CNS may represent undesirable side-effects of the treatment, and vice versa. The present invention seeks to avoid this problem by presenting 5-HT4 receptor agonists and antagonists which will not penetrate the blood-brain barrier and thus will not have access to 5-HT4 receptors located inside the CNS.
Moreover, the problem of poor targeting of 5-HT receptor ligands is aggravated by the fact that the receptor activity is diminished upon frequent binding. Unwanted or unselective binding is undesired in this context also.
Several modulators with affinity for 5-HT4 receptors are known in the state of the art. This includes agonists, antagonists and partial agonists. Modulators of 5-HT4 receptors are today in active development as potential therapeutic drugs.
U.S. Pat. No. 6,552,046 discloses the modification of the piperidinyl nitrogen of cisapride with a moiety wherein an acidic group may be in close proximity to the basic nitrogen. Moreover, despite recognising that cisapride has CNS side effects, it modifies cisapride with an ester moiety for purposes of avoiding cytochrome P-450 due to degradation of the ester by esterases. Most remarkably, U.S. Pat. No. 6,552,046 observes that cisapride enters the central nervous system and binds to 5-HT4 receptors, indicating that cisapride may have centrally-mediated effects. It further states compounds of U.S. Pat. No. 6,552,046 can be used in the treatment of: 1) cognitive disorders, including but not limited to Alzheimer's disease; 2) behavioural disorders, including but not limited to schizophrenia, mania, obsessive- compulsive disorder, and psychoactive substance use disorders; 3) mood disorders, including but not limited to depression and anxiety; and 4) disorders of control of autonomic function, including but not limited to essential hypertension and sleep disorders.
U.S. Pat. No. 6,624,163 (Pfizer) discloses imidazopyridines as 5-HT4 modulators. Notably, none of the embodiments of the invention comprise an acidic moiety. This recent attempt in the area of 5-HT modulators is silent to means of differentiation between 5-HT related CNS disorders to gastrointestinal or cardiac disorders. The novel compounds are directed to everything from neurological diseases to heartburn. Each of the embodiments of U.S. Pat. No. 6,624,163 are suitable substrates for modification with an acidic moiety according to the present invention.
U.S. Pat. No. 6,632,827 seeks to minimise side effects with the use of an optically pure form of norcisapride in the treatment of gastrointestinal disorders yet concerns itself with the associated serious CNS side effects such as memory loss, sleep disorders, depression, and psychoactive distress. Each of the embodiments of U.S. Pat. No. 6,632,827 are suitable substrates for modification with an acidic moiety according to the present invention US 2001/0031751 provides novel 5-HT4 antagonists, but does not seek to differentiate the CNS-from the peripherally-located receptors and thus intends their use in both CNS and gastrointestinal or cardiovascular disorders. Notably, none of the embodiments of the invention comprise an acidic moiety. Each of the embodiments of US 2001/0031751 are suitable substrates for modification with an acidic moiety according to the present invention.